Non-invasive system and method for measuring an analyte in the body

ABSTRACT

A system for determining an analyte concentration in a fluid sample (e.g., glucose) comprises a light source, a detector, and a central processing unit. The detector is adapted to receive spectral information corresponding to light returned from the fluid sample being analyzed and to convert the received spectral information into an electrical signal indicative of the received spectral information. The central processing unit is adapted to compare the electrical signal to an algorithm built upon correlation with the analyte in body fluid. The algorithm is adapted to convert the received spectral information into the analyte concentration in body fluid. Spectral information is delivered from the central processing unit to the light source and used to vary the intensity and timing of the light to improve the accuracy of conversion into analyte concentration.

FIELD OF THE INVENTION

The present invention relates generally to systems for the determinationof analytes by their interaction with infrared, visible, or ultravioletradiation. In some important applications, analytes in body fluids aremeasured, (e.g., non-invasive measuring of glucose in the body).

BACKGROUND OF THE INVENTION

Those who have irregular blood glucose concentration levels aremedically required to regularly self-monitor their blood glucoseconcentration level. An irregular blood glucose level can be brought onby a variety of reasons including illness such as diabetes. The purposeof monitoring the blood glucose concentration level is to determine theblood glucose concentration level and then to take corrective action,based upon whether the level is too high or too low, to bring the levelback within a normal range. The failure to take corrective action canhave serious implications. When blood glucose levels drop too low—acondition known as hypoglycemia—a person can become nervous, shaky, andconfused. Their judgment may become impaired and they may eventuallypass out. A person can also become very ill if their blood glucose levelbecomes too high—a condition known as hyperglycemia. Both conditions,hypoglycemia and hyperglycemia, are potentially life-threateningemergencies.

Common methods for monitoring a person's blood glucose level areinvasive in nature. Typically, to check the blood glucose level, a dropof blood is obtained from the fingertip using a lancing device. Theblood drop is produced on the fingertip and the blood is harvested usinga test sensor which is inserted into a testing unit. The test sensordraws the blood to the inside of the test unit which then determines theconcentration of glucose in the blood.

One problem associated with this type of analysis is that there is acertain amount of pain associated with the lancing of a finger tip.Diabetics must regularly self-test themselves several times per day.Each test requires a separate lancing, each of which involves aninstance of pain for the user. Further, each lancing creates alaceration in the users skin which take time to heal and are susceptibleto infection just like any other wound.

Other techniques for analyzing a person's blood glucose level arenoninvasive in nature. Commonly, such techniques interpret the spectralinformation associated with light that has been transmitted through orreflected from a person's skin. An advantage of this type of noninvasiveanalysis is that there is no associated pain or laceration of the skin.However, thus far, such techniques have proven unreliable because manytechniques fail to recognize the many issues that impact the analysis.For example, many noninvasive reflectance and transmission based systemsdo not account for the fact that the obtained spectral data containsglucose information from the portion of body tissue being analyzed as awhole, and is not limited to blood glucose. Other techniques do notaccount for irregularities in the spectral signal of the analyte dueinstrumental drift, temperature changes in the tissue under analysis,spectral characteristics of the tissue that change due to pressurechanges, etc. that can occur during the analysis or between analyses.These irregularities can impact the quality of the calibration model orthe algorithms that are used to determine the analyte concentrationsfrom the noninvasively collected spectral data. The spectral data thathas these irregularities cannot be used by the algorithms to determinethe analyte concentrations.

Accordingly, there exists a need for a reliable noninvasive system forthe determination of analytes in body fluids.

Near infrared radiation has been applied non-invasively in attempts toidentify the glucose content of a patient's blood. However, non-invasivemethods subject to the infrared radiation areas of the body that containblood vessels, but other fluids containing glucose are present. Aperson's skin contains glucose in the extracellular fluid, whichincludes plasma and interstitial fluid. Since measurements of glucose bynon-invasive methods are made in the dermis, they primarily determinethe glucose in the extracellular fluid, plus some glucose in bloodcontained in capillaries in the skin. What is wanted is a correlationwith the glucose content of blood, typically a small amount in thegeneral range of 50 to 450 mg/dL. Now, it will be evident that ifabsorption of infrared radiation at specific wavelengths that areassociated with glucose could be detected and measured, then the desiredinformation will have been obtained. In practice, the presence of waterand other materials that absorb infrared radiation make it difficult tomeasure the amount of glucose in the blood that is present and exposedto the infrared radiation. Some research has been directed to comparingthe absorption of infrared radiation at certain wavelengths with areference beam that has not been directed to the skin of a subject. Morecommonly, attempts have been made to correlate the response of a subjectto a broadband of infrared radiation with measurements made by reliablemethods of determining the glucose content of blood obtained by invasivemethods.

In some patents including U.S. Pat. Nos. 5,435,309 and 5,830,132,methods are described in which, rather than applying a broadband ofradiation or pre-selected wavelengths, a band of infrared radiation isscanned using acousto-optic tunable filters (AOTF). These solid statedevices permit rapid scanning of a band of radiation without usingfilters or moving parts. The response of the subject to the radiation isdetected and correlated using techniques familiar to those skilled inthe art such as, for example, partial least squares (PLS) and principalcomponent analysis (PCA).

In co-pending U.S. patent application Ser. No. 10/361,895 published asU.S. 2004/0092804A1, an improved method of measuring glucosenon-invasively that employs AOTF was disclosed. In addition to analgorithm developed to correlate the spectral information with directmeasurements of glucose in a subject's blood, the system employedseveral unique features that improved accuracy and consistency. Thosefeatures included a clamping device for assuring good contact with bodytissue and which provided precise temperature and pressure control atthe point of measurement. A unique attachment clamping device, includingsapphire rods, termed an optoid by the inventors, were provided todirect radiation into the measurement region and transmit light leavingthe region to the radiator detector. The device represented an advancein the art, but further improvement was sought by the present inventor.

It will be evident from the above discussion that obtaining accuratemeasurements of small amounts of glucose in blood by non-invasivemethods is difficult since the concentration of glucose is smallrelative to other materials in the sample area and its response toinfrared radiation occurs in regions in which other materials in higherconcentrations also respond. At least two important problems areinvolved. First, much of the incident radiation is absorbed or scatteredand the amount actually received by the detector is small. Thus,improving the signal-to-noise ratio is important. Second, water ispresent in large amounts relative to glucose and interferes withaccurate measurement of glucose. This is especially a problem withinstruments that employ a wide band of infrared radiation such asscanning and diode array instruments. As discussed above, instrumentsusing AOTF scan a predetermined radiation band. This makes possibleadjusting the power of the monochromatic light provided by the AOTFdevice so that the signal received at pre-selected wavelengths ismaximized across the entire spectral region. Due to the differentabsorbency and scattering characteristics of the skin in the infraredregion, the spectrum collected from the skin can have orders ofmagnitude differences in intensity. The limitations of most systems arethat they are not able to maximize the information quality across such adivergent spectral region. Improvement of the signal-to-noise rationwould be advantageous. Varying skin characteristics that affectscattering and absorbance of infrared radiation can be accounted for andthen the signal-to-noise ratio could be improved. Another improvement inan AOTF device would provide feedback to adjust the power and thescanning time to provide the most accurate results. Further improvementcould be obtained by programming the AOTF to change the amplitude of theradiation in specific regions of the spectrum that are obtained from aninteraction with a known glucose concentration. The information soobtained would help to characterize the scattering, absorbance, andinterference effects associated with a pure glucose sample.

The present inventor has found that an improved non-invasiveglucose-measuring instrument can be made employing the above-describedprinciples. Such an improved instrument will be described in detailbelow. Furthermore, the principles employed in the glucose-measuringinstrument may be applied more generally to measuring analytes in mayother instances.

SUMMARY OF THE INVENTION

In its more general aspects, the invention includes an instrument thatsupplies a source of infrared, visible, or ultraviolet light to a samplebelieved to contain an analyte and that retrieves returned lightreflected from or transmitted through the sample and determines theamount of the analyte by the absorption of the light. The non-invasivesystem for measuring glucose in the fluid in body tissue is one example.The light source may be an AOTF, laser diode array, a filtered broadband light source, or other sources that provide light in predeterminedwavelength regions to a sample being inspected. A central processingunit will control the supply of light to the sample and its measurementupon its return to a detector. The central processing unit will provideone or more sets of light spectra to improve accuracy of the conversionof the received spectral information into concentration of the analytein the sample. Light spectra may include one or more of the following,preferably in sequence.

-   -   a source of light in which each wavelength segment has equal        intensity over the wavelength range    -   a source of light in which the intensity of each wavelength        segment is adjusted to provide returned light having equal        intensity throughout the wavelength range    -   a source of light in which a sample is exposed to light of        predetermined wavelengths for varying times    -   a source of light in which a sample is exposed to light only at        wavelengths determined to have the least signal-to-noise ratio.    -   a source of light in which a sample is exposed to light at        wavelengths determined to have a high signal-to-noise ratio, but        at which significant information regarding the analyte is        believed to be present.    -   a source of light that contains information that corrects for        changes in the analyte-related spectrum by the sample, light        delivery and collection methods such as fibers or lenses, and        the detector distortions.    -   a source of light containing concentration-related spectra that        correct for non-linear responses of the analyte.

The results obtained with those light spectra that are intended toemphasize certain regions of returned light may also be achieved byusing a uniform intensity light source and processing the returninglight.

In one embodiment, the invention includes a system for determining theconcentration of an analyte in the fluids in body tissue (e.g., glucosein extracellular fluids) that comprises an infrared light source, amonochromatic device (e.g., an AOTF), a body tissue interface, adetector, and a central processing unit. The body tissue interface isadapted to contact body tissue and to deliver light from themonochromatic light source across a predetermined wavelength range tothe contacted body tissue. The detector is adapted to receive spectralinformation corresponding to infrared light transmitted through orreflected from the portion of body tissue being analyzed and to convertthe received spectral information into an electrical signal indicativeof the received spectral information. The central processing unit isadapted to compare the electrical signal to an algorithm built uponcorrelation with the analyte in body fluid, the algorithm adapted toconvert the received spectral information into the concentration of theanalyte in body fluids.

In one embodiment of the invention, the light is modulated to correspondwith a spectrum obtained by interaction of the light with a pure glucosesample.

BRIEF DESCRIPTION OF THE FIGURES

FIG. 1 is a diagram of a transmission-based system for determininganalytes in body fluids.

FIG. 2 is a plot of the absorbency of transmitted light versuswavelength of the transmitted light according to one embodiment of thetransmission-based system illustrated in FIG. 1.

FIG. 3 is a flow chart depicting a method for building a glucosecalibration algorithm.

FIG. 4 a is a diagram of the contact with the body of areflectance-based system for determining analytes in body fluids.

FIG. 4 b is a cross-sectional view taken generally along line 4 b-4 b ofFIG. 4 a.

FIG. 5 is a plot of the absorbency of reflection light versus wavelengthof the reflected light according to one embodiment of thereflected-based system illustrated in FIG. 4 a.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

In the discussion that follows, application of the general principles ofthe invention will be discussed with particular reference to thenon-invasive measurement of the glucose content of body fluids, a methodof commercial importance. Similarly, application of the methods of theinvention could be applied to analyzing other analytes in the bodyfluids, such as cholesterol, hemoglobin, creatinine, alcohol, bilirubin,albumin, total proteins, and globulins. However, it should be understoodthat the invention is not limited to that specific application, but itcan be applied in many other situations where analytes are determined bytheir interaction with infrared, visible, or ultraviolet light. Forexample, measuring glucose or other sugar molecules in fermentationprocesses.

Determining the glucose content of blood is commonly used to monitor theneed for medication or dietary changes in diabetic patients.Non-invasive methods of measuring glucose have been of interest, sincethey avoid the need for sampling blood. Thus, in one importantembodiment, the invention has application in non-invasive methods formeasuring glucose in body tissue and in which light is either passedthrough or reflected from body tissue.

Transmission-Based System

Referring to FIG. 1, a transmission-based non-invasive system 10 for thedetermination of analytes in body fluids is functionally illustrated.The system 10 uses near infrared light transmitted through a piece ofskin, such as the “web” of skin between a patient's index finger andthumb. Conventionally, a patient's glucose level measured in this way isreferred to as their blood-glucose level. However, the measurement isprincipally made of glucose in the interstitial fluid and inter-cellularmaterial. Accordingly, the present inventor prefers to refer to apatient's glucose level, which can be correlated with a patient's bloodglucose level, as will be seen.

Human skin consists of approximately sixty percent extracellularmaterial and 40% intracellular material. The extracellular materialcomprises approximately 30% plasma (blood) and about 70% interstitialfluid (“ISF”). Therefore, when examining the spectral characteristics ofglucose from infrared light that is transmitted though a patient's skin,all the glucose in that portion of skin is being measured, rather thanonly the glucose in a patient's blood. The largest portion of thetransmitted light is made up of light transmitted though ISF, and notblood plasma. Conversely, in an invasive setting where a 10 μl drop ofblood is obtained on a patient's finger tip, for example, the measuredglucose concentration primarily represents the concentration of glucosein that patient's blood, rather than in other fluids.

The system 10 is used to obtain transmitted spectral information from apatient for correlation with invasive measurements from the samepatient. For example, the system 10 is used in a test wherein theglucose concentration of the test subject is modulated to a plurality ofdifferent concentration levels. One such test is a glucose clamping testwhere the glucose level of the test subject is raised and lowered tovarious levels over the duration of the test. According to oneembodiment, the glucose clamping test is designed to bring the testsubject's glucose level to six plateau regions that range inconcentration from 50 to 300 mg/dL. Each plateau is separated by about50 mg/dL so that each region can be clearly distinguished. ISF andplasma samples are collected throughout the duration of the clampingtest. The samples are collected every five minutes and are analyzed forglucose content. This measurement is used to adjust the infusion ofglucose or insulin to maintain the glucose concentration of the plasmafor about twenty-five minutes at a particular targeted plateau region.The spectral data obtained over the course of the test are compared tothe actual glucose levels (determined using invasive techniques)obtained during the test. From this data, a calibration algorithm isbuilt to predict the actual glucose level of the patient based on thespectral characteristics of light transmitted through that patient'sskin. This calibration algorithm can then be incorporated into ahandheld version of the system 10 illustrated in FIG. 1.

Such a handheld instrument would enable a user to noninvasively monitorthe user's glucose concentration level. The user would contact theuser's skin with the instrument to obtain spectral information from theuser's skin. The instrument would then provide the user with a readingof the user's glucose concentration level a short time later. Sources ofmonochromatic infrared light include, for example, a Tungsten-Halogenlight and an acoustic-optic tunable filter (AOTF). Referring to FIG. 1,an acoustic-optic tunable filter (“AOTF”) spectrometer is showngenerally by dashed line 12. The AOTF spectrometer 12 outputs amonochromatic, modulated beam of light 14 into a fiber optic cable 16via a lens 18. The AOTF spectrometer 12 includes a light source 20.According to one embodiment, the light source 20 is a Tungsten-Halogenlight source, which is a low-cost, stable light source that outputs agood amount of light (e.g., 250 watts). Alternative light sourcesinclude light emitting diodes (“LED”), doped fibers including uraniumdoped fibers, and laser diodes. The light source produces a beam oflight 22 in the near-infrared region (i.e., having a wavelength ranging750-2500 nanometers). This light is used to provide a series ofmonochromatic beams that scan across the beam width.

Generally, the AOTF spectrometer 12 functions as an electronicallytunable spectral band-pass filter to output the monochromatic beam oflight 14 having wavelengths within a desired range. The AOTF 12 is asolid state electro-optical device that consists of a crystal 19 inwhich acoustic (vibrational) waves, at radio frequencies (“RF”) are usedto separate a single wavelength of light from the broadband lightsource. The wavelength selection is a function of the frequency of theRF applied to the crystal 19. The crystal 19 used in AOTF devices can bemade from a number of compounds. According to one embodiment of thepresent invention, the crystal comprises Tellurium Dioxide (TeO₂). TeO₂crystals providing good results for use with light in the 1200 to 3000nm spectral region. According to one embodiment, the crystal 19 is usedin a non-collinear configuration, wherein the acoustic and optical waves(paths) through the crystal 19 are at very different angles from eachother. Alternatively, collinear configured AOTF devices may be used. Atransducer (not shown) is bonded to one side of the crystal. Thistransducer emits vibrations (acoustic waves) when RF is applied to thetransducer.

As the acoustic waves pass from the transducer to the crystal 19, thecrystal 19 alternately compresses and relaxes resulting in a refractiveindex variation that acts like a transmission diffraction grating.Unlike a classical grating, however, the crystal only diffracts onespecific wavelength of light so it acts like a filter more than as adiffraction grating. The wavelength of the light that is diffracted isdetermined by a phase matching condition based on the birefringence ofthe TeO₂ crystal and the velocity and frequency of the acoustical waveand as well as parameters specific to the design of the AOTF. Thewavelength that is selected is varied by simply changing the frequencyof the applied RF. The diffracted light is directed into two first orderbeams that we call the positive and negative beams. The rest of theundiffracted light is passed through as undiffracted zero (0) orderbeam. The positive and negative beams are orthogonally polarized. Thepositive beam is delivered to the optoid as described below and thenegative beam is used as a reference beam to correct for variations inthe intensity of the light source or the efficiency of the AOTF asdescribed below. Alternatively, the positive beam could be split and aportion used as a reference, while the remainder is sent to the optoid.

According to one embodiment, the beam of light 14 output by the AOTFspectrometer has a resolution or bandwidth of from about four to aboutten nanometers (“nm”). This bandwidth is swept (back and forth) across awavelength range of about 1400 to 2500 nanometers. Put another way, theAOTF spectrometer 12 outputs light having a wavelength continuouslyranging between 1400 and 2500 nm and has a resolution of from about 4 toabout 10 nm. The timing of the sweep can range from several millisecondsto several seconds. A suitable AOTF spectrometer is available fromCrystal Technologies, Inc. of Palo Alto, Calif. as AOTF Model 2536-01.The AOTF spectrometer includes a RF driver, a mixer, and a low frequencyoscillator (not shown) for modulating the monochromatic beam of light 14at approximately 20,000 Hz. Although the light can be modulated at thisfrequency, others can be used to provide comparative results used torefine the corrections to the light spectra obtained.

A voltage control oscillator (not shown) provides the control of the RFfrequency. Separate circuitry (not shown) is used for modulation andpower control, which range from 0 to about 0.5 watts. A suitable voltagecontrol oscillator is available from the Inrad Corporation, Northvale,N.J., Model DVCO-075A010. The power is delivered to an acousticaltransducer that creates an acoustical wave that changes thecharacteristic of a birefringence crystal 19 so that full spectrum lightis separated to wavelengths associated with a particular frequency andthe rest of the light passes through as zero order light.

The crystal 19 of the AOTF spectrometer 12 splits the beam of light 22into the first beam 14 and a second beam 23. The second beam of light 23is directed to a reference detector 24 for measuring/recording the lightinput to the skin. Additionally, the reference detector 24measures/records the light 23 for instrument drift associated with thelight source and AOTF that can occur over time due to the length ofoperating time and change in temperature of the instrument over thattime period.

The light 14 output by the AOTF spectrometer 12 is directed into thelens 18 that reduces the diameter of the beam of light and focuses thebeam of light 14 into an end of the fiber optic cable 16. The lens 18effectively couples the AOTF spectrometer 12 to the fiber optic cable16. The fiber optic cable 16 is a low OH (i.e., preferably about 0.3parts per million or below (of water in silica) fiber optic cable whichhas low attenuation over the length of the cable. The higher the OHcontent, the greater the intrinsic absorbance of the fiber itselfespecially in the wavelength region above 2100 nm. According to anotherembodiment, the fiber optic cable has an OH of less than about 0.12 ppm.The quality of light input to the fiber optic cable 16 is substantiallymaintained when delivered to a patient's skin at an opposite end 33 ofthe fiber optic cable 16. The output end 33 of the fiber optic cable 16connects to a device the inventor has termed an optoid 34. Generally,the optoid 34 consists of the hardware that interfaces with thepatient's skin. The optoid 34 includes a first plate 46 and a secondplate 48, which are slideably clamped onto the tissue being analyzed,such as the web of skin 52 (“the web 52”) of a patient's hand betweenthe index finger and thumb. The optoid 34 includes a sapphire rod 42that delivers light from the fiber optic cable 16 to the web 52. Thesapphire rod 42, having a diameter of about three millimeters in oneembodiment, increases the diameter of the beam of light input to the web52. Fiber optic cables are typically limited in diameter to about twomillimeters. The larger diameter of the sapphire rod 42 provides aneffective means of coupling light that can be up to 3 mm in beamdiameter to be delivered to the skin. Delivering a wider beam of light(e.g., the 3 mm of the sapphire rod as opposed to the 2 mm diameter ofthe fiber optic cable) covers a larger area of skin which limits theimpact of small irregularities in skin properties. The sapphire rod 42is flush with the interior surface of the first plate 46.

The light that is directed into the web 52 via the sapphire rod 42 istransmitted through the web 52 and into a second sapphire rod 54 (also 3mm in diameter) disposed within the second plate 48. The light passingthrough the web 52 is generally represented by arrows 56. The amount oflight transmitted through the web 52 is very low. Typically, less thanabout two percent of the light exiting the first sapphire rod 42 entersinto the second sapphire rod 54. The light transmitted through the web52 is directed by the second sapphire rod 54 into a detector 58.According to one embodiment of the present invention, the detector 58 isan extended Indium Gallium Arsenate (“InGaAs”) detector having acircular active surface of three millimeters in diameter and provides aresponse across the 1300 to 2500 nm spectral region. Such a detector iscommercially available from the Hamamatsu Corporation. According to oneembodiment of the present invention, the reference detector 24 and thedetector 58 are the same type of detector. Examples of other types ofdetectors that can be used in alternative embodiments of the presentinvention include Indium Arsenide (“InAs”), Indium Selenide (“InSe”),Lead Sulfide (“PbS”), Mercury-Cadmium-Telluride (“MCT”), and DTGdetectors. Other types of detectors can be used depending on the desiredregion of the spectrum to be analyzed for determining the glucoseconcentration level. As is discussed in greater detail below inconnection with FIG. 2, glucose exhibits unique spectral characteristicsin the about 1450-1850 nm and the about 2200-2500 nm spectral range. Thedetector 58 generates an electrical signal indicative of the detectedtransmitted light, which is processed as is described in detail below.

In addition to providing a mechanism for transmitting light through theweb 52, the optoid 34 performs other mechanical functions. First, themoveable first and second plates 46,48 (also referred to as “jaws”)provide pressure to compress the web 52 to maintain a consistent opticalpath through the web 52. Compressing the web 52 brings a greaterconsistency to the testing process. According to one embodiment, theplates 46, 48 compress the tissue approximately six percent from itsoriginal thickness. Compressing the tissue also creates a flushinterface between the web of skin and the plates 46,48 by eliminatingair gaps between the web 52 and plates 46,48 so that the lighttransmitted from the first sapphire rod 42 directly enters the web 52.The optoid 34 includes a load cell 56 to measure the contact pressure onthe web of skin 52. During the analysis, pressure measurements andtemperature measurements are obtained so that irregularities associatedwith changes in pressure or temperature can be accounted for asdiscussed in greater detail below. Also, compressing the skin reducesthe “noise” created by pulsing of the blood through the region beinganalyzed.

Second, each of the plates 46,48 includes thermal-electric heaters (notshown) that heat the web 52 to a uniform temperature. According to oneembodiment of the present invention, the thermal-electric heaters heatthe web to about 100° F.±0.1° F. The thermal-electric heaters, which areincorporated into each of the plates, are able to provide very accuratetemperature control. Typically, the temperature differential between thesurface of skin and the interior ranges between 5-7° F. Heating the skinto a substantially uniform level significantly reduces scattering of thelight transmitted through the skin due to temperature gradientsresulting in a more consistent analysis. Additionally, heating the skinto about 100° F. expands the capillaries and increases the amount ofblood in the capillaries by approximately 300%, thus bringing moreglucose into the area of analysis.

As discussed above, the AOTF 12 modulates the wavelength of the beam oflight 14, which causes the beam of light transmitted through the skinvia the optoid 34 to be modulated. The modulation aids in resolving someof the issues associated with instrument drift that can affect thequality of the spectral information. The modulated, transmitted light isreceived by the detector 58 and the modulated transmitted light strikesthe active material of the detector 58 and is converted by the detectorinto an electrical current indicative of the light received. Accordingto one embodiment, the electrical signal generated by the detector 58 isamplified by an amplifier (not shown) and sent to a lock-in amplifier70, which demodulates the signal. A suitable lock-in amplifier 70 isavailable from Stanford Research Instruments, Model SR 810 DSP,according to one embodiment of the present invention. Alternativelystill, the lock-in amplifier is integrated into an integrated circuitboard comprising the described electrical hardware of the presentinvention.

An analog-to-digital converter 72 then digitizes the demodulated signal.According to one embodiment of the present invention, theanalog-to-digital converter is a sixteen-bit converter available fromNational Instruments Corporation of Austin, Tex. It is contemplated thatother analog-to-digital converters may be used. Alternatively,digitization is incorporated into an integrated circuit board comprisingthe described electrical hardware of the present invention. In otheralternative embodiments, the digitization is at an 18 bit or higher bitrate.

The spectral data are optionally passed through a first filter 74 toremove high frequency noise and then a second filter 76 to remove slowdrifting that occurs due to gradual changes in the patient's skin overthe course of the analysis, or drift observed in the instrument or theoptical fibers. Filtering the signal in this manner improves the overallsignal-to-noise ratio.

The signal is then passed on to a central processing unit (“CPU”) 78.The CPU 78 averages the received signal, resulting in approximately 500data sets taken each minute over approximately 500 minutes. The data aresaved with a tracking of the wavelength of the light input to the optoid34. The spectral signal is also stored along with the time associatedskin temperature, room temperature, pressure applied to the skin duringthe measurement, and blood pressure measurements. This information isuseful in determining whether any irregularities in the spectral signalare the result of changes in these types of factors and not the resultof changes in the glucose concentration. The data are then processed toimprove the signal-to-noise quality of the data and to remove artifacteffects that can corrupt the quality of the spectral data. According toalternative embodiments of the present invention, the processing toimprove the signal-to-noise ratio can be accomplished in a variety ofmanners. For example, in one alternative embodiment, the signal-to-noisequality of the signal is improved by using Wavelet transforms to removehigh frequency noise and low frequency baseline drift type of noise(i.e., irrelevant spectral variations that are determined by theinformation entropy corresponding to glucose levels). According toanother alternative embodiment, the signal-to-noise quality is improvedusing such classical methods such as Savitsky-Golay multipointsmoothing. In other embodiments, first derivative analysis can be usedto deal with baseline issues such as baseline drift type of noise.

Additionally, the noise in the signal is improved by removing spectralinformation that is not related to the relevant glucose informationaccording to alternative embodiments of the present invention. This isaccomplished by the application of a Genetic Algorithm for selectingwavelength regions that are the most related to the glucose changes andremoving others that are not. This process results in the development ofrobust calibration algorithms that significantly reduce overfittingissues. In still another alternative embodiments, Orthogonal SignalCorrection (“OSC”) is employed to aid in the removal of non-glucosespectral information from the signal. This approach has provenbeneficial in the removal of temperature and time drift related changeimprints on the glucose-related data. Changes in the skin tissue resultin changes in the scattering characteristics of the skin. Removing thedata related to pressure and temperature changes over the course of theanalysis results in a better calibration algorithm that results inbetter glucose predictions based on spectral data. Using a combinationapproach results in a more improved signal than using these differentapproaches individually. For example, the inventors have found that acombination of Wavelet processing and OSC has produced excellentresults. Additionally, the inventors have found that the use of GeneticAlgorithms in conjunction with OSC has produced excellent results.

Similarly, the reference detector 24 detects the beam of light 23, whichis indicative of the light 14 provided to the optoid, and produces a“reference signal.” The reference signal is processed in a mannersimilar to the signal produced by the detector 58.

Referring now to FIG. 2, a plot of the percentage of light transmittedthrough the web versus wavelength (nm) is shown. The peaks in the plotbetween from about 1500-1850 nm and about 2100-2400 nm show a hightransmission of light 56 though the tissue. The high absorbency outsidethese spectral ranges is due, in part, to absorption by the watercontained in the skin. The glucose in the skin is present, in largepart, where the water in the skin is located. Glucose exhibits uniquespectral characteristics within these two wavelength ranges. Morespecifically, 1600-1730 nm and 2100-2380 nm regions.

The present invention provides further improvement of thesignal-to-noise ratio of the signal-to-noise ratio of the signalreceived by the CPU. It will be recalled that the transmission of lightvaries as the wavelength of the light is varied by the AOTF (or other)source, as shown in FIG. 2. It has been found the large excursions abovethe base of the curve produce lower signal-to-noise ratios than would bedesired. In some regions of the spectrum, the peaks are twenty timeshigher than in other parts of the spectrum. Thus, in one aspect theimproved method of the invention the height of the peaks above the baseline is effectively reduced in high transmission regions by reducing theintensity of the light in the appropriate wavelength region to reducethe height of the peak, with the result that the signal-to-noise ratiois improved by maximizing the dynamic range of the instrument in thespectral regions of interest. To accomplish this result, the CPU 78 isprogrammed to feed-back to the AOTF 12 (FIG. 1) the previouslydetermined light transmitted at each wavelength and to reduce theintensity of the light in the region where peaks have been found.

Another improvement related to the feed-back of information to the AOTFis the modulation of the speed at which the wavelength range is scanned.Since valuable information is contained in the peaks of the transmissionversus wavelength curve (e.g., FIG. 2). The scanning rate can be reducedwithin the peak regions to assure that the most accurate data isobtained. This also has been found to improve the signal-to-noise ratio,by averaging or integrating the data in such regions.

Further improvement can be obtained by programming the AOTF to changethe amplitude of the radiation in specific regions of the spectrumdetermined by measuring the spectrum of a known composition, forexample, a pure glucose sample or glucose in known fluids. Theinformation obtained from such measurements would help to characterizethe scattering, absorbance, and interference effects on the spectrum ofglucose (or other analyte). The use of a glucose sample as a filterbetween the light source and the skin being tested may also be helpfulin determining individual skin characteristics in sources where theglucose spectrum could not be programmed in, e.g. broadband lightsources.

In combination, the two improvements just described have been shown toimprove the signal-to-noise by a factor of 10, compared to the method inwhich the intensity of the examining light 14 is constant and thescanning rate is uniform.

As mentioned above, during the glucose clamping test, in addition to thetransmitted spectral data, samples of blood and ISF are obtained fromthe test subject (e.g., the patient subjected to the test) to determinethe subject's actual blood glucose level. According to one example ofthe glucose-clamping test, the test is conducted over an approximately500 minute duration. The blood and ISF samples are obtained about every5 minutes, totaling about 100 samples. These values are theninterpolated over the 500 minute test duration, resulting in about 500glucose concentration values.

The digital spectral signal of the transmitted light is averaged everyminute and stored resulting in about 500 data sets over the course ofthe test duration. This data is then analyzed and processed (describedin greater detail below) to build a calibration algorithm for predictingthe actual glucose concentration level from an examination of thespectral characteristics of the transmitted light.

To obtain predicted values, it is necessary to build a calibrationalgorithm that predicts the glucose concentration from the transmittedspectral signal (i.e., the signal produced by the detector 58). Afterthe spectral signal is filtered by the high and low frequency filters74,76, the signal is normalized to correct for changes in the spectralsignal which are the results of spectral scattering of the light whentransmitted through the web 52 and due to the pressure effects of theoptoid 34 which is clamped to the web of skin 52. Failure to correct forthese changes may obscure the spectral information associated with theglucose. As stated above, less than approximately two percent of thelight input to the web of skin 52 is transmitted to the detector 58.Accordingly, it is important to account for these types of changes andirregularities that can lead to errors. The raw signal from the AOTFspectrometer described above is first normalized to constant energy,then mean centered to remove constant areas of the spectrum, creating anormalized, preprocessed series of spectra that are then checked foroutliers by standard methods well known in the art. Furtherpreprocessing by OSC reduction and wavelets analysis filtering are doneto enhance the glucose signal and to suppress the water and otherbackground signals. The resulting set of spectra is then used to build acalibration model by partial least squares (PLS) regression usingVenetian blinds cross-validation on a portion of the data describedabove or on all of the data. Alternative embodiments to the datapreparation described above involve other common methods for reductionor removal of background signal, including, but not limited to,first-derivative smoothing, second-derivative smoothing, wavelengthselection by means of genetic algorithms, wavelet processing, andprincipal components analysis. Alternative embodiments for thegeneration of calibration models can be realized by many different formsof regression, including principal components regression, ridgeregression or ordinary (inverse) least squares regression.

The calibration algorithm to predict the glucose concentration is thenbuilt from the normalized signal. An orthogonal signal correctionprocess is combined with the time associated temperature and pressureinformation to identify the parts of the spectrum that are associatedwith these factors and not strictly related to the changes in theglucose concentration. This process is used in combination with thecorrelated data (i.e., the invasively determined glucose concentrationsof the plasma and the ISF fluids) to filter out of the spectral datainformation that is associated with changes in the other measurementsand not with changes in the glucose. This results in a calibrationalgorithm that is much more clearly associated with the changes in theglucose concentration, and less with artifacts that happen to correlateto the glucose concentration. Other data improvement processes includethe use of more generic chemometric applications such as GeneticAlgorithms and Wavelet analysis to further refine the spectralinformation to the most efficient information. The Genetic Algorithm andWavelet analysis are able to select wavelengths in the spectrum that arespecifically related to glucose and to permit the calibration algorithmto focus on specific changes in the glucose concentration. The selectionis based on the area of the spectrum where the strongest glucose relatedpeaks are located, but also the spectral areas related to the changes inthe refractive index of the tissue due to changes in the tissueconcentration. This wavelength selection process results in retainingthe wavelength information that produces the best calibration algorithm.

Referring now to FIG. 3, a flow chart depicting a method of building theglucose calibration algorithm will be described according to oneembodiment of the present invention. Initially, as described above, aglucose clamping experiment is conducted wherein spectral information isobtained from the body tissue of at least a first and a second testsubject. This information is stored in a first data set 82 and a seconddata set 83. In one embodiment, each of the first and second data sets82, 83 includes spectral information obtain from a plurality of testsubjects. Other information such as body tissue temperature, pressureapplied to the body tissue, and the invasively determined glucoseconcentration levels are obtained from each of the test subjects atpredetermined intervals during the glucose clamping test.

A combined data set, consisting of spectral data from more than one testsubjects (e.g., data from the first and second spectral data sets 82,84), is prepared and used to generate a model useful for prediction ofglucose levels for all of the subjects contributing data. The rawsignals, stored in the first and second data sets 82, 84, from the AOTFspectrometer described above are first normalized at step 84 to constantenergy for data from each of the test subjects. Portions of the data foreach subject are then combined to form a single, combined spectral setat step 85, which is then mean centered at step 86 to remove constantareas of the spectrum, creating a normalized, preprocessed series ofspectra that are then checked for outliers by standard methods known inthe art. Further preprocessing by OSC reduction and wavelets analysisfiltering are done to enhance the glucose signal and to suppress thewater and other background signals. The resulting set of spectra is thenused to build a calibration model by partial least squares (PLS)regression as step 87 using Venetian blinds cross-validation on aportion of the data described above or on all of the data. Alternativeembodiments to the data preparation described above involve other commonmethods for reduction or removal of background signal, including, butnot limited to, first-derivative smoothing, second-derivative smoothing,wavelength selection by means of genetic algorithms, wavelet processingand principal components analysis. Alternative embodiments for thegeneration of calibration models can be realized by many different formsof regression, including principal components regression, ridgeregression or ordinary (inverse) least squares regression.

The PLS model, which was created at step 87, is applied to theorthogonal signal corrected, normalized first data set at step 89, whichresults in the glucose calibration algorithm at step 90. The glucosecalibration algorithm 90 is used to predict glucose concentration basedupon spectral information obtained from a test subject. Put another way,the glucose calibration algorithm is able to determine the glucoseconcentration of a test subject based upon the spectral information(e.g., transmitted or reflected spectral information) obtained from atest subject. The glucose calibration algorithm 90 is then applied tothe orthogonal signal corrected, normalized second data set at step 91for predicting the glucose contraction values of the test subject(s) ofthe second spectral data set 83 at step 92. The glucose concentrationvalues predicted at step 92 are then compared to the invasivelydetermined glucose concentration obtained during the glucose clampingtest to check the accuracy of the glucose calibration algorithm at step93.

In an alternative embodiment, building the glucose calibration algorithmalso includes applying a Wavelets analysis to each of the data setsafter OSC step 88, which filters the data. Additionally, in otheralternative embodiments, the spectral data sets 82, 83 include spectraldata modeled for glucose concentration levels which are outside therange of glucose concentration levels achieved during the glucoseclamping test. In one embodiment, the AOTF spectrometer 12 can be usedto create spectral data outside the ranges achieved during the glucoseclamping test.

Reflectance-Based System

Referring now to FIGS. 4 a and 4 b, a reflectance-based non-invasivesystem 90 for the determination of analytes in body fluids isillustrated. Briefly, the system 90 inputs near infrared light into aportion of a patient's skin, such as a forearm, and records the amountof light reflected from the skin to determine the patient's glucoselevel.

A monochromatic beam of light is input to a bundle 100 of fiber opticcables. While the bundle 100 of fiber optic cables depicted in FIG. 5 bshows two concentric circles or rows of fiber optic cables 101, anyreasonable number of rows of fiber optic cable can be used. Themonochromatic beam of light is generated in a manner similar to thatdescribed in connection with FIG. 1. An AOTF spectrometer (not shown)outputs a beam of light 94 having a resolution of four to ten nanometers(“nm”), which is swept (back and forth) across a wavelength range ofabout 2200-4500 nanometers to the fiber optic cable bundle 100. Thefiber optic cable bundle 100 delivers light 94 to an optoid 104. Theoptoid 104 consists of the hardware that interfaces with a patient'sskin. The optoid 104 includes a plate 106 having a window 108 formedtherein. Light 102 is directed through the window 108 onto the patient'sskin 110. According to one embodiment of the present invention, thewindow 108 is a sapphire window.

In use, the optoid 104 is brought into contact with a patient's skin 110such as the patient's forearm, such that skin 110 rests on the plate 106and window 108. Light 102 is directed through the window 108 into theskin 110. The light penetrates the skin 110 to a depth of about 300microns and is then reflected from inside the skin 110. The reflectedlight 112 is represented by arrows. The reflected light 112 is directedto a detector 114 via a sapphire rod 116 disposed within the fiber opticbundle 100. The reflected light 112 is detected by the detector 114 in amanner similar to the transmitted light 56 discussed in connection withFIG. 1.

According to an alternative embodiment of the reflectance-based,non-invasive system 90, only a portion of the fiber optic cables 101 areused to deliver light to the optoid 104, which varies the path length ofthe delivered light. For example, only an inner ring of fiber opticcables 101 is utilized according to one embodiment and only the outerring of fiber optic cables 101 are utilized according to anotherembodiment. Varying the path length of the delivered light allows thesampling of reflected light from different depths in the tissue.According to some embodiments, the various path lengths are used tocorrect for individual tissue characteristics such as scattering.

The optoid 104 of the reflectance-based non-invasive system 90 providestemperature control to the area of skin from which the reflectancesignal is being taken. According to one embodiment of the presentinvention, the plates 106 of the optoid include thermoelectric heatersfor heating the skin to approximately 100°±0.1° F. Again, heating theskin to uniform temperature reduces scattering of light, which is afunction of temperature. Additionally, as discussed above, heating theskin causes the capillaries to expand thus increasing the volume ofblood in the capillaries approximately three hundred percent.

According to one embodiment of the present invention, an index matchingmaterial 113 is disposed between the skin 110 and the window 108, formaintaining a constant and matched index for the light 102 directed intothe skin 110 and the light reflected from the skin 112. The indexmatching gel reduces large index of refraction changes that would occurnormally between skin and a gap of air. These large changes result inFresnel losses that are especially significant in a reflectance basedanalysis, which creates significant changes in the spectral signal.According to one embodiment of the present invention, the indexingmatching material is a chloro-fluoro-carbon gel. This type of indexingmaterial has several favorable properties. First, thechloro-fluoro-carbon gel minimally impacts the spectral signal directedthrough the gel. Second, this indexing matching material has a highfluid temperature point so that it remains in a gel-like state duringthe analysis and under test conditions. Third, this gel exhibitshydrophobic properties so that it seals the sweat glands so that sweatdoes not fog-up (i.e., form a liquid vapor on) the sapphire window 108.And fourth, this type of index matching material will not be absorbedinto the stratum corneum during the analysis.

The output of the detector 114 is filtered and processed in a mannersimilar to that described in conjunction with the above-describedtransmission-based system 10.

Referring now to FIG. 5, a plot of the absorption of light input to theskin versus wavelength is shown. As can be seen in FIG. 5, highabsorption is observed in the 1350-1550 nm and the 1850-2050 spectralrange.

The calibration algorithm for the reflectance-based system is built byapplying similar data processing techniques as discussed in connectionwith the transmission-based system.

Varying the Applied Light or the Returning Light to Improve Accuracy

Once it has been seen how the invention may be employed in an importantapplication, that is, the non-invasive determination of the glucosecontent of body fluid, the variations of the method may be more readilyunderstood, including their applications where similar problems arefound.

The proposed variations will be discussed first with reference to themeasurement of glucose in the presence of substantial amounts of water,which interferes with the measurement of small amounts of glucose. Theabsorption of light by glucose and water affects the returning light,that is the reflected light or the transmitted light. Since the glucoseand water have similar characteristics it is difficult to separate theabsorption due to glucose from that of water. This is especially aproblem when the analyte, glucose, is present in much smaller amountsrelative to water. In the present invention, either the light source ismanipulated by the central processing unit or the returning light isexamined after detection in a related manner.

Consider the case in which an AOTF is used as a source of light. Whileit is easier to appreciate the variations of the method when they areapplied to the use of an AOTF as the light source, it should beunderstood that other light sources may be used in instruments thatmeasure analytes by means of their absorption of light within certaincharacteristic ranges. In the simplest case, the sample is exposed tolight having a predetermined range of wavelengths. That range is sweptthrough in sequence with equal intensity applied at each wavelength.Such a process produces the results shown in FIGS. 2 and 5. Since it isknown that glucose (or another analyte) has certain characteristics,that is, it absorbs light at certain wavelengths more than others, theabsorption of light does not clearly distinguish glucose in the presenceof water without further manipulation of the data, as has been discussedearlier. The present invention also includes new processing steps thatfurther improve the accuracy of the results, since the light absorbed ismore easily characterized. The new processing steps are discussed asapplied to altering the light produced by an AOTF, but may be appliedsimilarly to processing of light returning from the sample to thedetector.

Once the results of a scan of the suitable range of light wavelengthswith uniform intensity is obtained, the central processing unit isprogrammed to repeat the scan, but with the intensity at each wavelengthadjusted during the repeat scan so that the returning light has equalintensity at each of the wavelengths examined. Such a procedure has theeffect of suppressing the relative absorption of water so that thesignal-to-noise ratio is improved, because the detector becomes moresensitive to the presence of glucose at its characteristic wavelengths.

A further improvement may be obtained by scanning the desired range ofwavelengths non-uniformly, that is, dwelling for longer periods atwavelengths identified as containing more useful information about theglucose, relative to water or to other interfering substances. Then, thereturning light can be given more importance in the mathematicalanalysis of the data.

Another variation of the scanning process examines only thosewavelengths where it has been found that the signal-to-noise ratio isthe highest, that is, where the interference of water and othersubstances is the least. The effect of absorption by glucose would belikely to be more clearly seen and therefore the accuracy of the resultswould be expected to be improved.

A related method would examine only certain regions in which it has beenfound that information on glucose is more readily distinguished fromwater or other interfering substances. For example, the absorption oflight by glucose and water broadly speaking occurs in similar regions.However, the response varies with temperature and it is thereforefeasible to distinguish between glucose and water in certain regionswhere their difference in absorption of light is more easily seen as thetemperature of the sample is varied.

The light source may also be supplied with information that corrects forchanges in the analyte-related spectrum caused by the sample, thedelivery and collection methods (e.g., fibers or lenses) and detectordistortions. If changes to the returning light related to the associatedequipment and the sample itself can be corrected for, determining theamount of the analyte can be done with improved accuracy.

For various reasons, the response of the analyte may not be as linear aswould be expected. Therefore, the light source may containconcentration-related spectra that correct for the non-linearly ofresponse.

It will be evident to those skilled in the art that some of the methodsjust discussed may be applied to the detection and analysis of datacontained in light returning from the sample. Furthermore, any one or upto all of the improved methods may be applied in order to improve thesignal related to the analyte and thus to increase the accuracy of theanalysis. Preferably, a sequence of these methods would be applied torefine the determination of the analyte to improve the accuracy of theresults.

While the present invention has been described with reference to one ormore particular embodiments, those skilled in the art will recognizethat many changes may be made thereto. Each of these embodiments andobvious variations thereof is contemplated as falling within the scopeof the invention.

Alternative Embodiment A

A system for determining the concentration of an analyte in a fluidsample, the system comprising:

a light source delivering light within a predetermined wavelength range;

a detector adapted to receive spectral information corresponding tolight returned from said fluid and to convert the received spectralinformation into an electrical signal indicative of the receivedspectral information; and

a central processing unit adapted to compare the electrical signal to analgorithm built upon correlation with the analyte in the body fluid, thealgorithm adapted to convert the received spectral information into theconcentration of said analyte in said fluid, the central processing unitcontrolling the light source and varying the intensity and timing of thedelivery of said light within said predetermined wavelength range toimprove the accuracy of conversion of the received spectral informationinto concentration of said analyte in said fluid.

Alternative Embodiment B

The system of Alternative Embodiment A wherein said light source is aseries of beams of monochromatic light that scan across thepredetermined wavelength range.

Alternative Embodiment C

The system of Alternative Embodiment B further comprising a referencedetector adapted to receive a portion of said series of beams ofmonochromatic light and to convert the received light into a referenceelectrical signal.

Alternative Embodiment D

The system of Alternative Embodiment C wherein said light source isadapted to modulate the monochromatic beams of light, and furthercomprising at least one lock-in amplifier electrically for demodulatingthe reference electrical signal and for demodulating the electricalsignal indicative of the received spectral information.

Alternative Embodiment E

The system of Alternative Embodiment B wherein said monochromatic lightis delivered to said fluid sample sequentially across a predeterminedwavelength range.

Alternative Embodiment F

The system of Alternative Embodiment E wherein the intensity of saidmonochromatic light is uniform over said predetermined wavelength range.

Alternative Embodiment G

The system of Alternative Embodiment E wherein the intensity of saidmonochromatic light is varied across said predetermined wavelength rangeto provide spectral information received from said sample having uniformintensity across said predetermined wavelength range.

Alternative Embodiment H

The system of Alternative Embodiment E wherein said monochromatic lightis delivered to said sample for predetermined periods of time atpredetermined wavelengths.

Alternative Embodiment I

The system of Alternative Embodiment H wherein said monochromatic lightis delivered to said sample at predetermined wavelengths where thesignal-to-noise ratio is the greatest.

Alternative Embodiment J

The system of Alternative Embodiment H wherein said monochromatic lightis delivered to said sample at predetermined wavelengths where saidanalyte is more readily distinguished from interfering substances.

Alternative Embodiment K

The system of Alternative Embodiment A wherein said light sourcedelivers to said sample predetermined wavelengths of light atpredetermined intensities and said spectral information returned fromsaid sample is processed to provide spectral information having uniformintensity at said predetermined wavelengths.

Alternative Embodiment L

The system of Alternative Embodiment A wherein said light sourcedelivers to said sample predetermined wavelengths of light atpredetermined intensities and said spectral information returned fromsaid sample is processed to provide spectral information atpredetermined wavelengths where the signal-to-noise ratio is thegreatest.

Alternative Embodiment M

The system of Alternative Embodiment A wherein said light sourcedelivers to said sample predetermined wavelengths of light atpredetermined intensities and said spectral information returned fromsaid sample is processed to provide spectral information at wavelengthswhere said analyte is more readily distinguished from interferingsubstances.

Alternative Embodiment N

The system of Alternative Embodiment A wherein said light sourcecontains information that is used to correct for the effect on the lightspectra of the sample, light delivery and collection systems, anddetector.

Alternative Embodiment O

The system of Alternative Embodiment A wherein said light sourcecontains information that corrects for changes in the analyte-relatedspectrum by the sample, light delivery and collection methods, anddetector distortions.

Alternative Embodiment P

The system of Alternative Embodiment A wherein said light sourcecontains concentration-related spectra that correct for non-linearresponses of the analyte.

Alternative Process Q

The method for determining the concentration of an analyte in a fluidsample, the method comprising the acts of:

delivering light within a predetermined wavelength range from a lightsource;

receiving spectral information corresponding to light returned from saidfluid;

converting the received spectral information into an electrical signalindicative of the received spectral information;

comparing the electrical signal to an algorithm built upon correlationwith the analyte in the body fluid; and

converting the received spectral information into the concentration ofsaid analyte in said fluid via a central processing unit,

wherein the central processing unit controls the light source and variesthe intensity and timing of the delivery of said light within saidpredetermined wavelength range to improve the accuracy of conversion ofthe received spectral information into concentration of said analyte insaid fluid.

Alternative Embodiment R

A system for determining the concentration of an analyte in body tissuefluid, the system comprising:

an infrared light source delivering substantially monochromatic lightsequentially across a predetermined wavelength range;

a body tissue interface adapted to contact body tissue and to deliverlight from said infrared light source to the contacted body tissue;

a detector adapted to receive spectral information corresponding toinfrared light transmitted through the contacted body tissue and toconvert the received spectral information into an electrical signalindicative of the received spectral information; and

a central processing unit adapted to compare the electrical signal to analgorithm built upon correlation with the analyte in the body fluid, thealgorithm adapted to convert the received spectral information into theconcentration of the analyte in the body fluid, said central processingunit controlling said infrared light source and varying the intensityand timing of the delivery of said monochromatic light within thepredetermined wavelength range to improve the accuracy of conversion ofthe received spectral information into concentration of said analyte insaid fluid.

Alternative Embodiment S

The system of Alternative Embodiment R wherein said infrared lightsource is an acoustic optical tunable filter (AOTF).

Alternative Embodiment T

The system of Alternative Embodiment S wherein said wavelength range isfrom about 1400 nanometers to about 2500 nanometers.

Alternative Embodiment U

The system of Alternative Embodiment R wherein said body fluid isextracellular fluid and said analyte is glucose.

Alternative Embodiment V

The system of Alternative Embodiment U wherein said infrared lightsource is modulated to correspond to a spectrum obtained by interactionof the infrared light with a pure glucose sample.

Alternative Embodiment W

The system of Alternative Embodiment U wherein the intensity of saidmonochromatic light is uniform over said predetermined wavelength range.

Alternative Embodiment X

The system of Alternative Embodiment U wherein the intensity of saidmonochromatic light is varied across said predetermined wavelength rangeto provide spectral information received from said sample having uniformintensity across said predetermined wavelength range.

Alternative Embodiment Y

The system of Alternative Embodiment U wherein said monochromatic lightis delivered to said sample for predetermined periods of time atpredetermined wavelengths.

Alternative Embodiment Z

The system of Alternative Embodiment Y wherein said monochromatic lightis delivered to said sample at predetermined wavelengths where thesignal-to-noise ratio is the greatest.

Alternative Embodiment AA

The system of Alternative Embodiment Y wherein said monochromatic lightis delivered to said sample at predetermined wavelengths where saidanalyte is more readily distinguished from interfering substances.

Alternative Embodiment BB

The system of Alternative Embodiment U wherein said monochromatic lightdelivers to said sample predetermined wavelengths of light atpredetermined intensities and spectral information returned from saidsample is processed to provide spectral information having uniformintensity at said predetermined wavelengths.

Alternative Embodiment CC

The system of Alternative Embodiment U wherein said monochromatic lightdelivers to said sample predetermined wavelengths of light atpredetermined intensities and said spectral information returned fromsaid sample is processed to provide spectral information atpredetermined wavelengths where the signal-to-noise ratio is thegreatest.

Alternative Embodiment DD

The system of Alternative Embodiment U wherein said monochromatic lightdelivers to said sample predetermined wavelengths of light atpredetermined intensities and said spectral information returned fromsaid sample is processed to provide spectral information at wavelengthswhere said analyte is more readily distinguished from interferingsubstances.

Alternative Embodiment EE

The system of Alternative Embodiment U wherein said monochromatic lightcontains information that is used to correct for the effect on the lightspectra of the sample, light delivery and collections systems, anddetector.

Alternative Embodiment FF

The system of Alternative Embodiment U wherein said light sourcecontains information that corrects for changes in the analyte-relatedspectrum by the sample, light delivery and collection methods, anddetector distortions.

Alternative Embodiment GG

The system of Alternative Embodiment U wherein said light sourcecontains concentration-related spectra that correct for non-linearresponses of the analyte.

Alternative Process HH

A method for determining the concentration of an analyte in body tissuefluid, the method comprising the acts of:

delivering substantially monochromatic light from an infrared lightsource sequentially across a predetermined wavelength range;

contacting body tissue with a body tissue interface;

delivering light from said infrared light source to the contacted bodytissue;

receiving spectral information corresponding to infrared lighttransmitted through the contacted body tissue;

converting the received spectral information into an electrical signalindicative of the received spectral information;

comparing the electrical signal to an algorithm built upon correlationwith the analyte in the body fluid using a central processing unit; and

converting the received spectral information into the concentration ofthe analyte in the body tissue fluid using the algorithm,

wherein the central processing unit controls said infrared light sourceand varies the intensity and timing of the delivery of saidmonochromatic light within the predetermined wavelength range to improvethe accuracy of conversion of the received spectral information intoconcentration of said analyte in said fluid.

Alternative Embodiment II

A system for determining the concentration of an analyte in body tissuefluid, the system comprising:

an infrared light source delivering substantially monochromatic lightsequentially across a predetermined wavelength range;

a body tissue interface adapted to contact body tissue and to deliverlight from said infrared light source to the contacted body tissue;

an index matching medium disposed between the body tissue interface andsaid body tissue, wherein the infrared light delivered to said bodytissue and reflected by the body tissue passes through said indexmatching medium;

a detector adapted to receive light reflected from the body fluid and toconvert the received reflected light into an electrical signalindicative of the received reflected light; and

a central processing unit adapted to compare the electrical signal to analgorithm built upon correlation with the analyte in the body fluids,the algorithm converting the received spectral information into theconcentration of the analyte in said body fluid, said central processingunit controlling said infrared light source and varying the intensityand timing of the delivery of said monochromatic light with thepredetermined wavelength range to improve the accuracy of conversion ofthe received spectral information into concentration of said analyte insaid fluid.

Alternative Embodiment JJ

The system of Alternative Embodiment II wherein said infrared lightsources is an optical tunable filter (AOTF).

Alternative Embodiment KK

The system of Alternative Embodiment JJ wherein the infrared light has awavelength ranging between approximately 1400 nanometers andapproximately 2500 nanometers.

Alternative Embodiment LL

The system of Alternative Embodiment II wherein said body fluid isextracellular fluid and said analyte is glucose.

Alternative Embodiment MM

The system of Alternative Embodiment LL wherein said monochromaticinfrared light is modulated to correspond to a spectrum obtained byinteraction of the light with a pure glucose sample.

Alternative Embodiment NN

The system of Alternative Embodiment LL wherein the intensity of saidmonochromatic light is uniform over said predetermined wavelength range.

Alternative Embodiment OO

The system of Alternative Embodiment LL wherein the intensity of saidmonochromatic light is varied across said predetermined wavelength rangeto provide spectral information received from said sample having uniformintensity across said predetermined wavelength range.

Alternative Embodiment PP

The system of Alternative Embodiment LL wherein said monochromatic lightis delivered to said sample for predetermined periods of time atpredetermined wavelengths.

Alternative Embodiment QQ

The system of Alternative Embodiment PP wherein said monochromatic lightis delivered to said sample at predetermined wavelengths where thesignal-to-noise ratio is the greatest.

Alternative Embodiment RR

The system of Alternative Embodiment PP wherein said monochromatic lightis delivered to said sample at predetermined wavelengths where saidanalyte is more readily distinguished from interfering substances.

Alternative Embodiment SS

The system of Alternative Embodiment LL wherein said monochromatic lightdelivers to said sample predetermined wavelengths of light atpredetermined intensities and spectral information returned from saidsample is processed to provide spectral information having uniformintensity at said predetermined wavelengths.

Alternative Embodiment TT

The system of Alternative Embodiment LL wherein said monochromatic lightdelivers to said sample predetermined wavelengths of light atpredetermined intensities and said spectral information returned fromsaid sample is processed to provide spectral information atpredetermined wavelengths where the signal-to-noise ratio is thegreatest.

Alternative Embodiment UU

The system of Alternative Embodiment LL wherein said monochromatic lightdelivers to said sample predetermined wavelengths of light atpredetermined intensities and said spectral information returned fromsaid sample is processed to provide spectral information at wavelengthswhere said analyte is more readily distinguished from interferingsubstances.

Alternative Embodiment VV

The system of Alternative Embodiment LL wherein said monochromatic lightcontains information that is used to correct for the effect on the lightspectra of the sample, light delivery and collections systems anddetector distortions.

Alternative Embodiment WW

The system of Alternative Embodiment LL wherein said light sourcecontains information that corrects for changes in the analyte-relatedspectrum by the sample, light delivery and collection methods, anddetector distortions.

Alternative Embodiment XX

The system of Alternative Embodiment LL wherein said light sourcecontains concentration-related spectra that correct for non-linearresponses of the analyte.

Alternative Process YY

A method for determining the concentration of an analyte in body tissuefluid, the method comprising the acts of:

delivering substantially monochromatic light using an infrared lightsource sequentially across a predetermined wavelength range;

contacting body tissue using a body tissue interface;

delivering light from said infrared light source to the contacted bodytissue;

placing an index matching medium between the body tissue interface andsaid body tissue, wherein the infrared light delivered to said bodytissue and reflected by the body tissue passes through said indexmatching medium;

receiving light reflected from the body fluid;

converting the received reflected light into an electrical signalindicative of the received reflected light;

comparing the electrical signal to an algorithm built upon correlationwith the analyte in the body fluids via a central processing unit; and

converting the received spectral information into the concentration ofthe analyte in said body fluid,

wherein the central processing unit controls said infrared light sourceand varies the intensity and timing of the delivery of saidmonochromatic light with the predetermined wavelength range to improvethe accuracy of conversion of the received spectral information intoconcentration of said analyte in said fluid.

While the invention is susceptible to various modifications andalternative forms, specific embodiments are shown by way of example inthe drawings and described in detail. It should be understood, however,that it is not intended to limit the invention to the particular formsdisclosed, but on the contrary, the intention is to cover allmodifications, equivalents, and alternatives falling within the spiritand scope of the invention as defined by the appended claims.

1. A system for determining the concentration of an analyte in a fluidsample, the system comprising: a light source delivering light within apredetermined wavelength range; a detector adapted to receive spectralinformation corresponding to light returned from said fluid sample andto convert the received spectral information into an electrical signalindicative of the received spectral information; and a centralprocessing unit adapted to compare the electrical signal to an algorithmbuilt upon correlation with the analyte in the body fluid, the algorithmadapted to convert the received spectral information into theconcentration of said analyte in said fluid sample, the centralprocessing unit controlling the light source and varying the intensityand timing of the delivery of said light within said predeterminedwavelength range to improve the accuracy of conversion of the receivedspectral information into concentration of said analyte in said fluidsample.
 2. The system of claim 1, wherein said light source is a seriesof beams of monochromatic light that scan across the predeterminedwavelength range.
 3. The system of claim 2, further comprising areference detector adapted to receive a portion of said series of beamsof monochromatic light and to convert the received light into areference electrical signal. 4.-12. (canceled)
 13. The system of claim1, wherein said light source delivers to said sample predeterminedwavelengths of light at predetermined intensities and said spectralinformation returned from said sample is processed to provide spectralinformation at wavelengths where said analyte is more readilydistinguished from interfering substances.
 14. The system of claim 1,wherein said light source contains information that is used to correctfor the effect on the light spectra of the sample, light delivery andcollection systems, and detector.
 15. The system of claim 1, whereinsaid light source contains information that corrects for changes in theanalyte-related spectrum by the sample, light delivery and collectionmethods, and detector distortions.
 16. The system of claim 1, whereinsaid light source contains concentration-related spectra that correctfor non-linear responses of the analyte.
 17. A method for determiningthe concentration of an analyte in a fluid sample, the method comprisingthe acts of: delivering light within a predetermined wavelength rangefrom a light source; receiving spectral information corresponding tolight returned from said fluid sample; converting the received spectralinformation into an electrical signal indicative of the receivedspectral information; comparing the electrical signal to an algorithmbuilt upon correlation with the analyte in the fluid sample; andconverting the received spectral information into the concentration ofsaid analyte in said fluid sample via a central processing unit, thecentral processing unit controlling the light source and varying theintensity and timing of the delivery of said light within saidpredetermined wavelength range to improve the accuracy of conversion ofthe received spectral information into concentration of said analyte insaid fluid sample. 18-50. (canceled)
 51. A method for determining theconcentration of an analyte in body fluid, the method comprising theacts of: delivering substantially monochromatic light using an infraredlight source sequentially across a predetermined wavelength range;contacting body tissue using a body tissue interface; delivering lightfrom said infrared light source to the contacted body tissue; receivinglight reflected from the body fluid; converting the received reflectedlight into an electrical signal indicative of the received reflectedlight; comparing the electrical signal to an algorithm built uponcorrelation with the analyte in the body fluid via a central processingunit; and converting the received spectral information into theconcentration of the analyte in said body fluid, wherein the centralprocessing unit controls said infrared light source and varies theintensity and timing of the delivery of said monochromatic light withthe predetermined wavelength range to improve the accuracy of conversionof the received spectral information into concentration of said analytein said fluid.
 52. The method of claim 51 further including disposing anindex matching medium disposed between the body tissue interface and thereceived body tissue, wherein the infrared light delivered to the bodytissue and reflected by the body tissue passes through the indexmatching medium.
 53. The method of claim 51, wherein the infrared lighthas a wavelength ranging between approximately 1400 nanometers andapproximately 2500 nanometers.
 54. The method of claim 51, wherein theintensity of said monochromatic light is uniform over said predeterminedwavelength range.
 55. The method of claim 51, wherein the intensity ofsaid monochromatic light is varied across said predetermined wavelengthrange to provide spectral information received from said sample havinguniform intensity across said predetermined wavelength range.
 56. Themethod of claim 51, wherein said monochromatic light containsinformation that is used to correct for the effect on the light spectraof the sample, light delivery and collections systems and detectordistortions.
 57. The method of claim 51, wherein said light sourcecontains concentration-related spectra that correct for non-linearresponses of the analyte.